Parkinson's disease is a progressive neurodegenerative disorder that is characterized by the loss of dopamine neurons in the substanfia nigra pars compacta, resulfing in severe motor symptoms, which include a tremor at rest, rigidity, bradykinesia, akinesia and postural instability. In addition to motor deficits, there are a variety of non-motor symptoms associated with Parkinson's disease, including olfactory deficits, problems with gastrointesfinal mofility, sleep disturbances, sympathefic denervafion, anxiety, and depression. One of the promising areas of Parkinson's disease therapeufics is the administrafion of growth factors, such as glial cell derived neurotrophic factor (GDNF) or brain-derived neurotrophic factor (BDNF). Unfortunately, trials with GDNF and BDNF have not been successful, which is due, in part, to drug delivery and pharmacokinefic limitations. In collaboration with the Ye laboratory at Emory University, we have identified a class of orally active TrkB agonists that appear to recapitulate many of the actions of BDNF. Here we propose to test these novel compounds for their ability to restore funcfion in several animal models of Parkinson's disease. Based on preliminary evidence, we hypothesize that our novel orally-active TrkB agonists will restore function in these animal models. To test this hypothesis we propose to determine the ability of the novel TrkB agonists to restore funcfion in the MPTP mouse model (aim 1), to determine the anfiparkinsonian efficacy of the TrkB agonists in a chronic and progressive animal model of the disease that displays motor and non-motor deficits (VMAT2 LO mice, aim 2), and to determine the ability of these compounds to activate TrkB and alleviate symptoms in a non-human primate model of PD. Complefion of these specific aims will help us to determine the potential utility of selecfive and orally-acfive TrkB agonists as a therapeufic intervenfion for Parkinson's disease and posifion us to apply for further support from the NINDS Translafional Research Program

Public Health Relevance

Parkinson's disease afflicts over one million U.S. citizens. Current dopaminergic treatments have limited efficacy, and often problematic side effects. This project is designed to test a new potential therapeutic intervenfion for the treatment of Parkinson's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS071669-04
Application #
8539097
Study Section
Special Emphasis Panel (ZNS1-SRB-E)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$202,408
Indirect Cost
$68,382
Name
Emory University
Department
Type
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Smith, Yoland; Galvan, Adriana (2018) Non-human primate research of basal ganglia and movement disorders: advances and challenges. J Neural Transm (Vienna) 125:275-278
Porter-Stransky, Kirsten A; Centanni, Samuel W; Karne, Saumya L et al. (2018) Noradrenergic Transmission at Alpha1-Adrenergic Receptors in the Ventral Periaqueductal Gray Modulates Arousal. Biol Psychiatry :
Masilamoni, Gunasingh J; Smith, Yoland (2018) Chronic MPTP administration regimen in monkeys: a model of dopaminergic and non-dopaminergic cell loss in Parkinson's disease. J Neural Transm (Vienna) 125:337-363
Sanders, Teresa H (2017) Stimulation of Cortico-Subthalamic Projections Amplifies Resting Motor Circuit Activity and Leads to Increased Locomotion in Dopamine-Depleted Mice. Front Integr Neurosci 11:24
Huddleston, Daniel E; Langley, Jason; Sedlacik, Jan et al. (2017) In vivo detection of lateral-ventral tier nigral degeneration in Parkinson's disease. Hum Brain Mapp 38:2627-2634
Chen, Erdong; Paré, Jean-Francois; Wichmann, Thomas et al. (2017) Sub-synaptic localization of Cav3.1 T-type calcium channels in the thalamus of normal and parkinsonian monkeys. Brain Struct Funct 222:735-748
Lv, Xiaohui; Dickerson, Jonathan W; Rook, Jerri M et al. (2017) M1 muscarinic activation induces long-lasting increase in intrinsic excitability of striatal projection neurons. Neuropharmacology 118:209-222
Cliburn, Rachel A; Dunn, Amy R; Stout, Kristen A et al. (2017) Immunochemical localization of vesicular monoamine transporter 2 (VMAT2) in mouse brain. J Chem Neuroanat 83-84:82-90
Masilamoni, Gunasingh Jeyaraj; Groover, Olivia; Smith, Yoland (2017) Reduced noradrenergic innervation of ventral midbrain dopaminergic cell groups and the subthalamic nucleus in MPTP-treated parkinsonian monkeys. Neurobiol Dis 100:9-18
Dunn, Amy R; Stout, Kristen A; Ozawa, Minagi et al. (2017) Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson disease. Proc Natl Acad Sci U S A 114:E2253-E2262

Showing the most recent 10 out of 99 publications